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Tetra-Cyclic Carboline Derivatives Useful in the Inhibition of Angiogenesis

Inactive Publication Date: 2008-07-31
PTC THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]In one embodiment, the invention is directed to methods for inhibiting VEGF production comprising administering a VEGF-expression inhibiting amount of at least one compound of the invention to a subject in need thereof.
[0017]In another embodiment, methods for inhibiting angiogenesis are provided comprising administering an anti-angiogenic amount of at least one compound of the invention to a subject in need thereof.
[0018]In yet another embodiment, methods for the treatment of cancer, d

Problems solved by technology

Although all of these approaches show significant inhibition of angiogenesis in vivo, they all possess significant limitations.
For example, therapeutic proteins (antibody and soluble receptors) or oligos (antisense, siRNA and ribozyme) are large molecules with poor permeability that usually require parenteral administration and are costly to produce.
For treatment of chronic ocular neovascularization, multiple injections may be impractical due to potential complications such as retinal detachment and procedure related infection.
Moreover, tyrosine kinase inhibitors have the potential for limited specificity.

Method used

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  • Tetra-Cyclic Carboline Derivatives Useful in the Inhibition of Angiogenesis

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Compounds of the Invention

[0112]Compounds of Formula I may be prepared according to Scheme I. By way of example, Compounds 23, 33, 35 and 40 may be prepared as follows. Other preferred compounds of the invention, such as those in Table 4 below, may be similarly prepared.

example 1a

Synthesis of Compound 2 (Racemic)

[0113]

[0114]In accordance with Scheme I, p-anisaldehyde (2.16 g, 15.9 mmol, 1.93 mL) is added to a suspension of 5-Bromotryptophan (3 g, 10.6 mmol) in 100 mL of Acetic acid at room temperature. The reaction mixture is then heated to reflux at about 125° C. in silicon oil bath and maintained at that temperature for about 3 hours 20 minutes. The resulting solution is concentrated under vacuum. The residue is triturated with dichloromethane, diethyl ether and hexane to yield powdery brown solid. The resulting acid salts of the desired product are then collected and washed with hexane three times and then, used for next step without purification.

[0115]The collected brown solid is suspended in 60 ml of acetone. The suspension is treated with triethylamine (14.37 mmol, 2 mL) and cyclohexyl isothiocyanate (2.03 g, 14.37 mmol, 2.04 mL) to give a homogenous solution. The reaction mixture is refluxed for about 2.5 hours at about 70° C., and then concentrated u...

example 1b

Synthesis of Compound 14

[0116]

[0117]In accordance with Scheme I, p-anisaldehyde (0.18 ml, 1.5 mmol) is added to 5-bromotryptophan (283 mg, 1.0 mmol) in AcOH (1.5 ml) and heated to about 110° C. in a capped tube. The solids are dissolved upon heating. After about 2.5 h, the reaction mixture is cooled to room temperature and concentrated on rotavap. The thick oil residue is stirred in CH3CN (2 ml) and a brownish solid precipitated out. The solid is filtered and washed with CH3CN (2×) to give 5 as a light brown powder, 0.20 g, 50% yield. The product was 95% pure by LC-MS, contaminated with 3% of 4 and 2% of p-anisaldehyde, and it is used without further purification. MS (ES+) m / z: 401 / 403.13, Rt: 2.45 min.

[0118]To a solution of 5 (55.5 mg, 1.5 mmol) in 2-butanone (1.5 ml) and TEA (0.2 ml) is added cyclohexylisocyanate. The mixture is heated at 100° C. in a capped tube. After 2 h, the reaction mixture was cooled to room temperature, concentrated on rotavap. The residue was chromatograph...

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Abstract

In accordance with the present invention, tetracyclic caboline derivatives that inhibit the expression of VEGF post-transcriptionally have been identified, and methods for their use provided. In one aspect of the invention, these compounds useful in the inhibition of VEGF production, in the inhibition of angiogenesis, and / or in the treatment of cancer, diabetic retinopathy or exudative macular degeneration are provided. In another aspect of the invention, methods are provided for the inhibition of VEGF production, the inhibition of angiogenesis, and / or the treatment of cancer, diabetic retinopathy or exudative macular degeneration using the compounds of the invention.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of and priority to U.S. Provisional Application No. 60 / 552,724, filed Mar. 15, 2004, which application is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to methods and compounds for inhibiting angiogenesis. More particularly, the present invention relates to methods and compounds for inhibiting angiogenesis.BACKGROUND OF THE INVENTION[0003]Aberrant angiogenesis plays a critical role in the pathogenesis of numerous diseases, including malignant, ischemic, inflammatory and immune disorders (Carmeliet, Nat. Med., 9(6):653-60 (2003), Ferrara, Semin. Oncol., 29(6 Suppl 16):10-4 (2002)). The best-known of these disorders are cancer, exudative macular degeneration and diabetic retinopathy (DR), the last two of which are leading cause of blindness in the United States (Witmer et al., Prog. Retin Eye Res., 22(1):1-29 (2003), Clark et al., Nat. Rev. Drug Discovery, 2:448...

Claims

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Application Information

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IPC IPC(8): A61K31/437A61K31/4166A61P43/00
CPCA61K31/4166C07D235/02C07D221/18C07D241/04C07D265/30C07D307/78C07D317/48C07D239/26A61P3/04A61P9/00A61P9/10A61P17/00A61P17/06A61P19/02A61P27/00A61P27/02A61P29/00A61P35/00A61P43/00
Inventor MOON, YOUNG-CHOONCAO, LIANGXIANTAMILARASU, NADARAJANQI, HONGYANCHOI, SOONGYULENNOX, WILLIAM JOSEPHCORSON, DONALD THOMAS
Owner PTC THERAPEUTICS INC
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